Intrathecal 4-Hydroperoxycyclophosphamide: Neurotoxicity, Cerebrospinal Fluid Pharmacokinetics, and Antitumor Activity in a Rabbit Model of VX2 Leptomeningeal Carcinomatosis

Dissemination of tumor to the leptomeninges and cerebrospinal fluid represents a common pattern of metastasis for many cancers; however, few chemotherapeutic agents are available for intrathecal (i.t.) use and treatment results are often poor. We studied the neurotoxicity and pharmacokinetics of i.t. 4-hydroperoxycyclophosphamide (4-HC) in the rabbit and the activity of i.t. 4-HC in a VX2 rabbit model of leptomeningeal carcinomatosis to evaluate the potential use of 4-HC in the treatment of leptomeningeal tumors. Toxicity studies examined 4-HC doses ranging from 0.5 to 6.0 jimol administered by intraventricular injection weekly for 4 to 8 weeks. Clinical or histological neurotoxicity was not observed in rabbits treated with < 1.0 umo\ 4-HC for 4 weeks. Clinical toxicity, characterized by lethargy, weight loss, seizures, or death, was apparent at doses >2.0 umol. Vasculitis of superficial arteries was observed in rabbits treated with >1.0 Mmol 4-HC. In cerebrospinal fluid pharmacokinetic studies, the mean drug half-life after intraventricular or in-tralumbar administration was 24.3 and 18.2 min. Regional inequities in drug exposure were apparent as area under the clearance curve values for cerebrospinal fluid distant from the injection site were lower than those of proximate sites (P < 0.001). Weekly intraventricular treatment of VX2 leptomeningeal tumor-bearing rabbits with 0.5 or 1.0 Mmol of 4-HC resulted in an increased life span of 22.5 and 35%, respectively. These results indicate that i.t. 4-HC, at doses lower than those producing neurotoxicity in the rabbit, is effective treatment for VX2 leptom-eningeal carcinomatosis.